The dopamine (DA) system is intimately involved in neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder (ADHD). Antipsychotics are often D2-like DA receptor blockers that compete with endogenous DA while ADHD is commonly treated with methylphenidate that inhibits DA transporter (DAT). Among the brain areas, the striatum has the densest DA innervation and the heaviest expression of DA receptors and DAT, indicating the importance of striatal DA signaling in brain functions. The striatal basal extracellular DA concentration ([DA]ext) is often estimated to he static and only 5-10 nM, which may increase by several fold upon external stimulation. Other transmitters, such as glutamate, can be spontaneously released from synaptic vesicles (quantal release), resulting in dynamic transmitter profiles with peaks up to I mM. We have evidence supporting the hypothesis that in the striatum DA can he spontaneously released in a similar quantal fashion, giving rise to a dynamic DA profile with high [DA]ext spikes. Our preliminary data also suggest that these spontaneous vesicular DA events are enhanced by antipsychotics and methylphenidate at clinically relevant low concentrations. Selective serotonin reuptake inhibitors (SSRIs) are an effective treatment for depression. Our data support the following hypothesis: during SSRI type antidepressant treatment, serotonin (5-HT) may be reuptaken by DA transporter (DAT) and accumulate in DA terminals in the striatum, a major DA projection area participating in reward/motivation. More importantly, this ectopically stored 5-HT may be co-released with DA, thus inducing a spatially and temporally synchronized DA and 5-HT co-signaling in the striatum. Following these working hypotheses, our goals are to use fast cyclic voltammetry at carbon fiber microelectrodes to investigate the striatal DA dynamics, its modulation and its interaction with the 5-HT system. The results will provide important new information about the dynamic nature of the striatal [DA]ext and its regulation by therapeutic agents of neuropsychiatric disorders.